The Vinca alkaloids, a group of dimeric indoledihydroindoles, have achieved considerable prominence as marketed or experimental chemotherapeutic drugs for the treatment of susceptible carcinomas, sarcomas, and leukemias. These agents are used both alone and in combination with other oncolytic agents. As a class, the Vinca alkaloids include compounds obtainable from the leaves of Vinca rosea, derivatives produced by chemical modification thereof and more recently, dimeric alkaloids produced by coupling two "monomeric" indoles via a modified Polonovski reaction-see Langlois and Potier, Tetrahedron Letters, 1099 (1976), Potier, et al., J.C.S. Chem. Comm., 670 (1975), Kutney et al., Heterocycles, 3, 205 (1975) and Atta-ur-Rahman, Tetrahedron Letters, 2351 (1976).
A majority of the known Vinca alkaloids can be represented by the following formula: ##STR1##
In the above formula, where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vinblastine is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" (4'-deoxyvinblastine) but R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" (4'-deoxyleurosidine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine is represented; and where R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are the same as in leurosine but R.sup.2 is formyl, leuroformine (N-formylleurosine) is represented.
The above-mentioned alkaloids are described in the following publications: leurosine (vinleurosine--U.S. Pat. No. 3,370,057), VLB (vincaleukoblastine, vinblastine--U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and vincristine (leurocristine or VCR) (both in U.S. Pat. No. 3,205,220), and deoxy VLB "A" and "B", Tetrahedron Letters, 783 (1958). Other alkaloids obtainable from vinca rosea include 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (2'-hydroxy VLB--U.S. Pat. No. 3,890,325) and vicadioline (3'-hydroxy VLB--U.S. Pat. No. 3,887,565).
Two of the above alkaloids, VLB and vincristine, are now marketed as drugs for the treatment of malignancies, particularly the leukemias and related diseases in humans. Of these marketed compounds, vincristine is a most active and useful agent in the treatment of leukemias but is also the least abundant of the antineoplastic alkaloids of Vinca rosea. Jovanovics et al.--U.S. Pat. No. 3,899,493--have developed an elegant oxidative procedure for converting the more abundant alkaloid VLB to vincristine employing chromic acid in acetone and acetic acid at about -60.degree. C. The same procedure has been used to prepare leuroformine (N-formylleurosine) from leurosine--see Belgian patent No. 811,110. Leuroformine is currently undergoing a clinical trial in Europe, chiefly in treatment of the leukemias and of multiple myeloma.
Chemical modification of VLB and vincristine has included hydrolysis of the 4-acetoxy group to yield 4-desacetyl VLB (DAVLB) or 4-desacetylvincristine (DAVCR) followed by reesterification with other acyl and amino-acyl groups--see U.S. Pat. Nos. 3,392,173 and 3,387,001--, and replacement of the C-3 ester function by an amide function--see Belgian patent 837,390. One of the former 4-acyl derivatives, the 4-N,N-dimethylglycine ester underwent a brief clinical trial and one of the latter, vindesine, (4-desacetyl VLB C-3 carboxamide) is currently being tested clinically against a variety of neoplasms.
Other chemical modification of the VLB molecule such as hydrolysis and decarboxylation of the C-18' carbomethoxy group has resulted in a loss of anti-cancer activity as has the formation of N-oxides; i.e., pleurosine (leurosine N-oxide). Oxidative attack on VLB under reaction conditions different from those of Jovanovics (loc. cit.) has resulted in the formation of a chemotherapeutically-inactive compound, vinamidine, which alkaloid has also been encountered in alkaloidal fractions from Vinca rosea leaves--see Tafur et al. J. Pharm. Sci., 64, 1953 (1975).
It is an object of this invention to prepare derivatives of oncolytically active Vinca alkaloids having either a different anti-tumor spectrum, or lessened or different side effects, or both as compared with the marketed drugs, vinblastine and vincristine.